Thyroid-specific enhancer-binding protein, T/EBP is a homeodomain-containing transcription factor that regulates expression of thyroid and lung-specific genes, including those encoding thyroid peroxidase, thyroblogulin, TSH receptor, and the Na/I symporter in the thyroid, and surfactant proteins A, B, and C, and clara cell secretory protein in the lung. T/EBP is expressed in the thyroid, lung, and ventral forebrain during early embryogenesis, suggesting that T/EBP may play a role in genesis of these organs. A mouse lacking T/EBP expression is missing the thyroid and pituitary, and has severe defects in lung and hypothalamus. The establishment of T/ebp -null mouse line, thus, unequivocally demonstrated that T/EBP is essential during development, and provides an excellent animal model to study how the lung, thyroid, pituitary, and hypothalamus are formed. Based on the detailed histological, immunohistochemical, and in situ hybridization analyses of the defects in T/ebp -null mouse, T/EBP appears to qualify as a master regulatory gene involved in morphogenesis of the thyroid, lung, and pituitary, which either activates or suppresses downstream target genes, ultimately leading to organ development. Our efforts have focused on identifying genes that are regulated by T/EBP during mammalian development and that are involved in organogenesis. To this end, we have carried out PCR-based subtraction library screening using lungs obtained from wild-type and T/ebp -null mouse embryos. We have identified two novel genes that are lung-specific and directly or indirectly under the regulation of T/EBP. We named one gene an uteroglobin-related protein since it has amino acid sequence similarity to uteroglobin/clara cell secretory protein gene family of proteins. The other gene encodes a tight-junction protein. Both of them are expressed during embryogenesis, suggesting that they may play a role in lung morphogenesis. Detailed analyses on promoter activities of the genes, the spatial and temporal expression patterns of mRNAs and proteins, and characterization of proteins are currently in progress, in order to understand the function of these two novel gene products.